Primary eosinophilic gastrointestinal disorders and allergy: Clinical and therapeutic implications

Abstract Primary eosinophilic gastrointestinal disorders (EGID) are increasingly prevalent, immune‐mediated, chronic conditions which primarily affect pediatric and young adult patients, leading to substantial disease burden, and poor quality of life. EGID may either involve single portions of the gastrointestinal tract (i.e., esophagus, stomach, small bowel, and colon) or a combination. Their strong association with allergic disorders has been recently recognized, and although their shared pathophysiological basis remains partly elusive, this feature greatly impacts the diagnostic and treatment work‐up. We herein critically discuss the current knowledge on the association of EGID and allergic disorders, including atopic dermatitis, allergic rhinitis, allergic asthma, and food or drug allergy. In particular, we reviewed the literature focusing on their epidemiology, pathophysiological basis and mechanisms, and diagnostic strategies. Finally, we discuss the currently ongoing clinical trials targeting EGID and allergic diseases, including, among others the monoclonal antibodies dupilumab, mepolizumab, benralizumab, and lirentelimab.

with a prevalence of 0.5 to 1/1000 individuals in the general population, is the most frequent among EGID, and hence it is the most studied. 7 It represents the most common cause of chronic dysphagia in children and the most common cause of dysphagia with bolus impaction in adults. 8 In a recent study by Cianferoni et al. conducted in the United States, the prevalence of concomitant atopic diseases was significantly higher in both adults and children, compared to non EoE patients. 9 Due to their supposed rarity and the paucity of data, the prevalence of the other disorders belonging to the EGID spectrum is more difficult to ascertain. According to a recent US registry-based study by Dellon et al., the prevalence of eosinophilic gastritis, gastroenteritis and eosinophilic colitis, after the introduction of specific ICD-9 codes, can be estimated to be as high as 6.3/100,000, 8.4/100,000, and 3.3/ 100,000, respectively. 10 However, this figure is probably underestimated, as this commonly occurs in administrative data-driven studies. 11 As recently reported in a systematic review with metaanalysis, non-esophageal EGIDs affect about 2% of patients referred to the hospitals for gastrointestinal symptoms and the prevalence of atopic comorbidities ranges from 25% to 54% of affected patients. 12 Eosinophilic esophagitis is a chronic immune-mediated, antigendriven, disease, and results from the complex interplay between genetic and environmental factors, also including early life exposures to certain factors, leading to epithelial barrier dysfunction, allergic sensitization, and prominent Th2 inflammation. 8,13,14 On the contrary, the pathogenesis of EGID not affecting the esophagus is still largely uncertain. Some cellular and molecular features of Th2 inflammation have been demonstrated, particularly with reference to eosinophilic gastroenteritis, but autoimmune factors are also believed to exert a role. 15,16 However, a comprehensive view of their pathogenesis is still lacking, and this contributes, along with other factors, to the substantial diagnostic delay and therapeutic uncertainty. 17,18 Moreover, the association with allergic disorders must be considered when managing patients with EGID, as they may share a common etiopathological background and hence some clinical features. 2,9,17 In fact, some patterns of disease association are common in these patients, such as the co-occurrence of allergic asthma, rhinitis, and esophageal symptoms, or the occurrence of gastrointestinal symptoms in patients receiving oral immunotherapy for food allergy, or else the occurrence of isolated diarrhea in atopic patients. 6,19,20 All these clinical patterns should raise the suspicious of EGID.
Apart from the common association with allergic manifestations, the clinical features of EGID vary according to the gut segment and the layer of the gut wall involved, that is, the mucosa, the muscular layer, or the serosa, and the diagnostic work-up of EGID is primarily based on endoscopy and histopathology. 21 The main clinical features, diagnostic criteria, and currently available therapies for EGID are summarized in Table 1.
The aim of the present review is to provide in a narrative and concise fashion an updated overview about the association between EGID and the whole spectrum of allergic disorders in adults and children, in order to improve diagnosis and treatment of allergic comorbidities in patients with EGID. We also provide a critical update of the ongoing clinical trials regarding therapies for EGID, highlighting potential advantages for concomitant allergic disorders.

| METHODS
In June and September 2021, we performed a computer-assisted literature search for relevant studies using PubMed. The aim of the search was to find papers dealing with the association of EGID with allergic disorders, focusing on the clinical and therapeutical implications. The research was restricted to papers published in English. The medical subject heading terms used were "EoE," "eosinophilic gastritis," "eosinophilic gastroenteritis," "eosinophilic colitis," and "atopy," "asthma," "allergic rhinitis," "atopic dermatitis," "drug allergy," "eczema," "environmental allergy." By using these terms, we found more 3000 papers. Of these, most were unrelated to the review topic and hence were discarded by all authors. We focused on the original, review articles, and case reports/series since database inception, dealing with the association of allergic disorders in EGID, in both the pediatric and the adult settings. We also searched for relevant papers cited in authoritative reviews dealing with EGID in relation to other allergic disorders. Given the narrative, expertbased, nature of the review we did not carry out a systematic review of the literature.

| Eosinophilic esophagitis
Eosinophilic esophagitis has proteiform manifestations and symptoms, which vary with age. 4 While young children and toddlers usually experience vomiting, regurgitation, abdominal pain, feeding refusal, and failure to thrive, adolescents and adults often report dysphagia and food impaction that may be the expression of advanced tissue remodeling. [22][23][24] EoE may affect people of any age and gender, but it is more common in young male individuals. It is characterized by the presence of esophageal infiltration in both the proximal and distal esophagus. The disrupted function of the muscolaris mucosa layer, which can be shown by ultrasonography, results in symptoms of esophageal dysmotility. 25 Most of the studies considering the relationship between EGID and asthma are focused on EoE, probably because EoE is the most frequent form of EGID, paralleling the epidemiologic surge of allergic diseases. 7,26 Several studies have shown that patients with EoE suffer from a significant burden of allergic comorbidities, such allergic rhinitis, asthma, atopic dermatitis, and IgE-mediated food-allergy.
The prevalence of asthma in adult series of EoE patients varies from 25% to 50%, and reaches 60% in pediatric series. [26][27][28] Moreover, in a previous meta-analysis considering a large number of individuals it was found that patients with EoE had a significantly increased probability of having asthma (OR 3.01, 95% CI 1.96-4.62, OR 5.09, 95% CI 3.91-8.90, respectively) and allergic rhinitis compared to controls. 29 This strong association has led some authors to consider EoE as "the asthma of the esophagus." 30 Food allergy has been traditionally linked to EoE, given the strong epidemiologic link between these disorders, the clinical and histological response of EoE to elemental diets, and, more recently, the increased recognition of EoE in patients being treated with oral immunotherapy. 8 The prevalence of IgE-mediated food allergy varies between 25% and nearly 70%. 29 Overall, these findings have led many researchers to include EoE in the spectrum of disorders making up the atopic march, often representing the final step of this progression. 32 Of note, the association between food allergy and EoE has been found to be the strongest. 32 Several pathophysiological theories have been put forward to explain the association between EoE with atopic disorders, however a consistent picture is still lacking. 33 A possible role of aeroallergens in terms of EoE diagnosis/exacerbation has been suggested by clinical studies, showing an association between pollen season and incidence of EoE diagnosis. 34 Besides, cases of EoE after sublingual immunotherapy for respiratory allergies have also been observed. 20,35,36 The exact mechanistic interpretation of these findings is still incomplete. A direct effect of pollen allergens, but also of food allergens that are cross-reactive to pollens, could be present.
A common pathophysiologic feature of EoE and food allergy could be the presence of a shared allergen-restricted Th2 specificity.
However, despite these similarities, these conditions display peculiar features, as EoE is usually a life-long disease, whereas food allergy is usually transitory, so it is not uncommon to encounter patients with EoE with a history of food allergy. Moreover, the anti-IgE therapy seems to exert a marginal role in EoE. 37,38 These findings imply that the eosinophilic inflammation in EoE is independent of a classical Th2-response and other still unknown factors play a role.  Table 1, depending on which layer of the gut wall is mostly affected.

| Eosinophilic gastritis and gastroenteritis
Symptoms could be mild and often overlooked, or could be serious and potentially life-threatening, including abdominal pain, diarrhea, and frank malabsorption. 39 Asthma and other allergic diseases, such as allergic rhinitis, have also been described in patients with eosinophilic gastritis or gastroenteritis, but with less convincing evidence compared to EoE. Nonetheless, the frequency of self-reported allergic rhinitis and asthma is still relevant, as high as 63% and 39%, respectively, in a questionnaire-based registry study assessing the prevalence of atopic conditions in 107 patients, adults and children, with these conditions. 40 More recently, some case reports have described the association between asthma and eosinophilic gastritis in a few patients with severe asthma, treated with dupilumab or mepolizumab. 41

T A B L E 3 Studies describing the association between eosinophilic gastrointestinal disorders and allergic disorders in children
Author The presence of food allergy was ascertained in a pediatric US series in one-ninth of patients with isolated eosinophilic gastritis and onethird in those with eosinophilic gastritis with duodenal eosinophilia. 43 in an another US study including 44 patients, children and adults, with eosinophilic gastroenteritis (associated EoE in 30% of the cases) the prevalence of food allergy was 42%. Interestingly, drug allergy was also found in 31% and eczema in 16%. 44 Overall, the prevalence of atopic disorders in patients with eosinophilic gastritis and gastroenteritis appears to be high, being estimated at 38.5% and 45.6%, respectively. 10

| Eosinophilic colitis
Primary eosinophilic colitis is the least frequent disorder among EGID. The absence of internationally agreed diagnostic criteria, including a clear eosinophilic infiltrate threshold, has hampered its identification for a long time. Eosinophilic colitis frequently presents with diarrhea, abdominal pain, anorexia, and weight loss. It has a bimodal age presentation, namely in infancy (at approximately 60 days of age) and during adolescence and early adulthood. 45 Also, it has been associated with a wide range of atopic disorders, including drug allergy, allergic rhinitis, asthma, and food allergy. 46,47 In a US administrative database study, Jensen et al. evaluated 404 adult patients with eosinophilic colitis, finding that co-existing allergic conditions were common, being present in 41.8% of the patients. 10 The most commonly reported allergic condition was allergic rhinitis (30%). Asthma was reported in 15% and atopic dermatitis in 6.2% of the patients. In a smaller series of adult patients (n = 22), a lower incidence of both asthma and allergic rhinitis (18%) was reported. 47 The prevalence of atopic conditions seems to be high also in children, according to the only case series available, which includes almost 50 individuals, and reports that 40% displayed one or more signs of atopy. 48 The same estimate of comorbid atopic conditions has been calculated by Dellon et al. in the aforementioned registerbased study. 10

| OUTLOOK
Allergic manifestations are a frequent comorbidity in patients with immune-mediated disorders of the gastrointestinal tract, including classical autoimmune diseases and EGID. 49 The current evidence of the association between EGID and allergic disorders, as discussed above, is summarized in Tables 2-4,  pathways that, in some cases, are shared with allergic diseases. For example, dupilumab, an anti-interleukin 4 (IL4) receptor alpha monoclonal antibody, has already been approved for the treatment of atopic dermatitis and allergic asthma, while mepolizumab, an anti-IL5 monoclonal antibody, has already been approved for allergic asthma. 78,79 Moreover, lirentelimab, a monoclonal antibody targeting an inhibitory receptor Siglec-8, could represent an interesting therapeutical agent targeting both the allergic disorders and EGID, since this receptor is present only on mastcells, basophils, and eosinophils, all key players in both disease groups. 18,80,81 The main molecular targets of monoclonal antibodies are shown in Figure 1.
We do feel that EGID and allergic disorders should be better managed by a multidisciplinary team, given their complex nature, which is not only confined to their possible shared pathophysiological bases, but also includes (i) the high clinical burden, due to their  Table 6. 82

ACKNOWLEDGMENT
We thank University of Pavia (PRIN2017) for supporting our research projects.